Niels Mørk

Stereoselective Enzymatic Hydrolysis of Various Ester Prodrugs of Ibuprofen and Flurbiprofen in Human Plasma

The hydrolysis kinetics of various alkyl, glycolamide, aminoethyl, and 2-(l-imidazolyl)ethyl esters of ibuprofen and flurbiprofen in 80% human plasma were investigated using a direct high-performance liquid chromatographic assay for the enantiomers of these acids. In each case, the R-isomer ester was found to undergo faster plasma-catalyzed hydrolysis than the corresponding S-isomer. The difference in the hydrolysis rates between the enantiomeric forms ranged from a factor of 1.4 for the N, N -diethylglycolamide ester of ibuprofen to a factor of 50 and 25 for the 2-(l-imidazolyl)ethyl ester of ibuprofen and flurbiprofen, respectively. Therefore, enantioselective differences in plasma-catalyzed ester prodrug hydrolysis must be taken into account when evaluating prodrugs of racemic mixtures of chiral drugs.

Phenyl carbamates of amino acids as prodrug forms for protecting phenols against first-pass metabolism

Abstract Various phenyl carbamate esters derived from amino acids, a dipeptide and amino acid esters and amides were prepared and assessed as potential prodrugs with the aim of protecting phenolic drugs against first-pass metabolism following peroral administration. The stability of the derivatives was studied in aqueous buffer solutions and in various biological media. The carbamates were rather stable in weakly acidic solutions but were hydrolyzed more facilely at physiological pH, the rates increasing greatly with decreasing p K a value of the phenol. The hydrolysis of the amino acid carbamates was not catalyzed significantly by liver or intestinal wall enzymes but human plasma showed a marked catalytic effect. This latter effect could predominantly be ascribed to a catalysis exhibited by serum albumin. These results suggest that derivatization of phenolic drugs to form α-amino acid or dipeptide carbamate esters may be a potentially useful prodrug approach to reduce the extent of first-pass metabolism of the vulnerable phenol group.

Enhanced delivery of nalidixic acid through human skin via acyloxymethyl ester prodrugs

Abstract Nalidixic acid has recently been suggested as a potentially useful agent for the treatment of psoriasis. In an attempt to improve the dermal delivery characteristics of nalidixic acid various esters of the compound were synthesized and assessed as prodrug forms for the parent drag. The esters studied include the methyl ester, a glycolamide ester and several acyloxylmethyl esters. Whereas the former two esters were only partly converted to the parent drug during diffusion through human skin samples, the acyloxymethyl derivatives were completely converted by enzymatic hydrolysis. Among the latter derivatives the butyryloxymethy) and the isobutyryloxymethyl esters showed a 5–6-fold enhanced delivery of nalidixic acid from both polar and apolar vehicles relative to application of nalidixic acid itself. The enhanced transport was suggested to be a result of the increased water and lipid solubilities of the ester derivatives in comparison to the parent drug.

Metabolism of Testosterone During in Vitro Transport Across CACO-2 Cell Monolayers: Evidence for β-Hydroxysteroid Dehydrogenase Activity in Differentiated CACO-2 Cells

Testosterone has previously been used as a model compound for the determination of unstirred water layer thickness in the CACO-2 transport model. We have found, however, that testosterone is metabolized during in vitro transport across the CACO-2 cell monolayers. This suggests that testosterone is not an ideal model substance. Testosterone is metabolized to androstenedione, indicating the formation of 17-β-hydroxysteroid dehydrogenase by differentiated CACO-2 cells. No reverse metabolism is observed, thus androstenedione is considered superior to testosterone for determination of unstirred water layer thickness in the CACO-2 system. Permeability coefficients for testosterone and androstenedione obtained under identical transport conditions were 66 (±7) * 10 −6 (n = 26) and 84 (±7) * 10−6 (n = 9) cm/sec, respectively. The unstirred water layer thicknesses at different agitation rates are determined for the CACO-2 transport model used in our laboratory utilizing androstenedione as a model compound. The system is capable of controlling the water layer thickness from about 200 to 1000 µm.

Evaluation of phenyl carbamates of ethyl diamines as cyclization-activated prodrug forms for protecting phenols against first-bass metabolism

Abstract A series of phenyl N -(2-aminoethyl)carbamates derived from various substituted ethyl diamines and phenol was prepared and evaluated as prodrug forms with the aim of protecting phenolic drugs against first-pass metabolism. The stability of the compounds was studied in aqueous buffer solutions and in various biological media. The compounds showed a high stability at lower pH but degraded by a cyclization process at higher pH values with a quantitative release of the parent phenol. The rate of cyclization was not affected by plasma, liver or gut enzymes but depended on the pH value of the medium and on the steric properties of the various substituents. By appropriate selection of the substituents, it is readily feasible to obtain prodrug derivatives having useful rates of cyclization, and hence release of the parent phenolic drug at pH 7.4 and 37°C, corresponding to half-lives of 10–60 min. The results suggest that this prodrug principle involving a non-enzymatic but pH-dependent conversion may be a potentially useful approach to reduce the extent of first-pass metabolism of the vulnerable phenol group.

Hemiesters of aliphatic dicarboxylic acids as cyclization-activated prodrug forms for protecting phenols against first-pass metabolism

Abstract Various hemiesters of aliphatic dicarboxylic acids and paracetamol or phenol were prepared and assessed as potential prodrug forms with the aim of protecting phenolic drugs against first-pass metabolism after peroral administration. The degradation of the hemiesters was studied in aqueous buffer solutions and in various biological media. In buffer solutions the derivatives degraded via an intramolecular ring-closure reaction in addition to acid- or base-catalyzed ester hydrolysis. At physiological pH (7.4) the intramolecular ring-closure reaction is the major reaction contributing to the overall degradation and half-lives in the range of 1–350 min at pH 7.4 and 37°C were determined for the studied derivatives. The half-lives depended upon the degree of substitution in the acid moiety, the size of the formed anhydride and the p K a value of the patent phenol. Liver homogenates clearly catalyzed the degradation of the hemiesters, whereas plasma showed different results for the esters of paracetamol and phenol, respectively. The only derivative not subjected to any enzymatic catalysis was the hemi-3,3-dimethylglutarate of paracetamol. Although highly substituted hemiesters might be useful prodrugs for certain individual phenolic drugs, derivatization of phenolic drugs into hemiesters may not be a generally useful prodrug approach for protection against first-pass metabolism, due to the fact that the derivatives are subjected to marked enzymatic catalysis in liver homogenates.

Furosemide prodrugs: synthesis, enzymatic hydrolysis and solubility of various furosemide esters

Abstract Various esters of furosemide were prepared and assessed as potential prodrugs with the aim of enhancing the peroral absorption characteristics of the parent drug. The esters studied included a neutral alkyl ester, alkyl esters containing an amino group, glycolamide esters and an O -acyloxymethyl ester. The esters showed widely different susceptibilities to undergo enzymatic hydrolysis in human plasma and rat liver homogenate, the propionyloxymethyl ester being the most reactive compound. The amino-containing esters were most soluble in water whereas all the esters were more lipophilic than furosemide as expressed by octanol-pH 7.4 buffer partition coefficients.

Kinetics of the decarboxylation of foscarnet in acidic aqueous solution and its implication in its oral absorption

Abstract The kinetics of decarboxylation of the antiviral foscarnet (trisodium phosphonoformate) to form carbon dioxide and phosphorous acid was studied in aqueous solutions at 37°C over the pH range 0.2–3.6, using a direct spectrophotometric method as well as an HPLC procedure. The variation of the rate of degradation with pH could be accounted for in terms of a spontaneous decarboxylation of the undissociated acid form of foscarnet with a first-order rate constant of 0.10 min −1 . Half-lives for the degradation were 29 min, 231 min and 51 h at pH 1, 2 and 3, respectively. It was estimated that in the gastric pH range 1–2 and with a gastric emptying half-time of 50 min, 18–63% of an ingested dose would be decomposed in the stomach. It is concluded that intragastric degradation may be of significance for the absorption of foscarnet upon peroral administration.